Glioblastoma multiforme (GBM) is a high-grade glioma and the most common primary malignant brain tumor.1 GBMs are diffuse and infiltrating with no clear border between normal brain and tumor. Current treatment regimens that include temozolomide have significantly improved the median, 2- and 5-year survival compared to radiotherapy alone in patients with newly diagnosed GBM.2,3 Nevertheless, GBM patients have a poor prognosis with a median survival of 14.6 months.2 The inherent or acquired resistance of tumor cells to antitumor agents and the highly invasive nature of tumor cells are the major impediments to the currently employed anti-GBM therapies and pose an urgent need for novel therapeutics with substantial efficacy. Oncolytic herpes simplex virus (oHSV) and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) have recently shown promise in both preclinical and clinical trials.4,5,6,7,8,9,10,11,12,13 Oncolytic viruses are genetically modified viruses that, upon infection, selectively replicate in and kill neoplastic cells while sparing normal cells.4,8,14 Among them, oHSV type 1-derived virus is one of the most extensively studied and considered a promising agent for treating brain tumors as well as other types of cancer. Recombinant oHSV vectors such as G207 and G47Δ have been previously investigated in both preclinical and clinical studies.9,16,17,18 Unlike replication-incompetent vectors, replication-competent or conditional vectors can amplify to produce virus progeny that then infects surrounding tumor cells resulting in multiple waves of infection in situ, virus spread and extensive cell death. In a direct comparison between oncolytic adenovirus and oHSV in GBM cell lines, oHSV was shown to be more efficacious.19 Mutations of specific HSV genes, namely γ34.5 and UL39, have been shown to confer selectivity to cancer cells, which has enabled translational studies to humans.4,15 Although phase 1 and 1b clinical trials for oHSV proved its safety, the efficacy for human GBMs seems marginal as only a subset of patients showed decrease in tumor volume9 which could in part be due to the insensitivity of a subset of GBM cells to HSV mediated oncolysis.
TRAIL has emerged as a promising antitumor agent due to its tumor-specific induction of apoptosis in a death receptor-dependent manner.20 Both recombinant human TRAIL ligand and TRAIL receptor agonist monoclonal antibodies are currently being evaluated in clinical trials,21 however, short half-life and off-target toxicity of systemically delivered TRAIL pose challenges in the clinic.22 It has previously been established that a secreted form of TRAIL (S-TRAIL) exerts more potent apoptotic effects compared to TRAIL itself and when delivered by viruses or different stem cell types has significant antitumor effects as compared to systemically administrated TRAIL in different mouse models of GBMs.5,7,10,11,12,23 However, malignant GBMs show heterogeneity in their response to TRAIL; with ˜50% showing sensitivity to TRAIL-mediated apoptosis and others showing varying resistance to TRAIL-mediated apoptosis.7-24 